# Targeting MNK Pathways in Pancreatic Cancer

> **NIH VA I01** · JESSE BROWN VA MEDICAL CENTER · 2020 · —

## Abstract

The dismal mortality rate for pancreatic ductal adenocarcinoma (PDAC) is attributed to the fact that it is a
highly chemo-resistant and aggressive cancer. Current therapies have also not been able to eradicate cancer
stem cells (CSCs), which can reestablish tumors following treatment. Notably, PDAC tumors are associated
with intensely collagen-rich stroma that we have shown can mediate epithelial-mesenchymal transition (EMT)
and contribute to cancer cell invasion. PDAC tumors are also associated with dys-regulation of mRNA
translation. We have provided evidence that PDAC cells in 3D collagen activate MNK kinases to mediate
eIF4E phosphorylation and regulate mRNA translation of EMT regulators. The long-term goal is to contribute
toward the development of novel mechanism-based targeted therapies for the treatment of PDAC. The main
objective in this application is to determine how MNK kinases mediate tumor development and progression in
vivo. The central hypothesis is that targeting MNK kinases will decrease PDAC tumor growth and metastasis
and suppress the CSC population. A second hypothesis is that targeting MNK kinases will lead to remodeling
and normalization of the stroma in PDAC tumors. These hypotheses are based on extensive preliminary data
demonstrating that MNK inhibitors decrease invasion in 3D collagen, suppress growth of human PDAC
organoids, decrease mRNA translation of the EMT activators ZEB1 and Snail, decrease the CSC population,
and decrease collagen production by stellate cells. Three specific aims are proposed: 1) Determine the role of
MNK kinases in PDAC progression in organoid and mouse models; 2) Evaluate the role of MNK kinases in
regulating pancreatic CSCs; and 3) Determine the role of MNK kinases in regulating the stromal reaction in
vivo. Under the first aim, the relative contribution of MNK1 and MNK2 to tumor progression in human PDAC
organoids, and in orthotopic and transgenic mouse models, will be determined. Their roles in enhancing mRNA
translation of EMT regulators and other pro-tumorigenic MNK target genes will be evaluated. For the second
aim, studies will be performed to evaluate the effects of MNK kinase targeting on pancreatic CSCs using in
vitro and in vivo assays, and the individual contributions of MNK1 and MNK2 to the regulation of CSCs and
CSC-regulating genes will be dissected. In the third aim, the mechanism by which MNK inhibitors regulate
stellate cell activation and collagen production will be determined. In addition, the ability of MNK inhibitors to
remodel and normalize the fibrotic stroma in mouse models will also be evaluated. There are several
innovative elements in this proposal, including the identification of signaling pathways that can be targeted to
eliminate CSCs in PDAC tumors and the use of a unique combination of complex models of pancreatic cancer,
including in vitro organoid cultures and in vivo orthotopic and transgenic models, to delineate the role of MNK
kinases in PDAC progression. ...

## Key facts

- **NIH application ID:** 9898302
- **Project number:** 5I01BX002922-04
- **Recipient organization:** JESSE BROWN VA MEDICAL CENTER
- **Principal Investigator:** Hidayatullah G. Munshi
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898302

## Citation

> US National Institutes of Health, RePORTER application 9898302, Targeting MNK Pathways in Pancreatic Cancer (5I01BX002922-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898302. Licensed CC0.

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